The purpose of this proposal is to determine how peptides from the amino terminal portion of human growth hormone are involved in potentiating insulin action at the level of the receptor. The specific aims are as follows: 1) Determine if in different types of insulin resistance, insulin binding to its receptors on monocytes and adipose tissue is enhanced by the peptides. 2) Determine if insulin-stimulated biochemical events at the receptor level are influenced by the pituitary peptides. Reactions to be examined are a) insulin degradation and/or internalization, b) changes in number of receptors, c) phosphorylation of the subunits of the insulin receptors, and d) enhancement of production of mediator peptides whose formation is under insulin control. 3) Determine whether different portions of the amino terminus of hGH act preferentially on different tissues in enhancing insulin binding. Liver and adipose tissue from the rat will be compared in the first experiments. 4) Determine whether the peptides enhance the IGF-1 and insulin activity in vitro in cultured cells (human fibroblasts) and rat cartilage. The study of the insulin potentiating action of amino terminal peptides from hGH arose from the observation that hGH20K lacks the early insulin-like properties of hGH. This variant is missing a 15 amino acid segment (residues 32-46) which subsequently was found to have insulin potentiating properties by itself. Although insulin potentiating activity has been reported for hGH peptides by four other laboratories, the concept has received little attention. The work proposed in this application provides a new approach to the study of the involvement of growth hormone fragments in modulating unsulin action. Preliminary work indicates that the hGH peptides enhance insulin binding to its receptor, a reaction that may account for their insulin potentiating properties. Examination of the mechanism of this reaction is important in evaluating potential therapeutic use of the peptides for treatment of insulin resistance. The project offers the hypothesis that insulin resistance results from an insufficiency of the insulin potentiating fragments of growth hormone. The studies with insulin stimulated cell growth will indicate whether the GH peptides have a general action and whether the peptides may be previously unrecognized growth factors.